Gonadotropin-releasing hormone (GnRH) is a decapeptide synthesized and released from neurons within the hypothalamus which acts on its own receptors in the anterior pituitary, thus accounting for the biosynthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Luteinizing hormone controls steroid synthesis in the male and female gonads while follicle-stimulating hormone is involved in the spermatogenesis in males and the development of ovarian follicles in females. Controlling GnRH, GnRH agonists or antagonists have attracted intensive attention for their therapeutic availability in the treatment of GnRH-related diseases, particularly, prostate cancer, breast cancer, endometriosis, leiomyoma, precocious puberty, and in the treatment of sterility.
Currently available therapeutics for the treatment of gonatrophin-related diseases use peptides which exhibit receptor antagonism by two different mechanisms. In one mechanism, they act as GnRH receptor agonists that interact with the gonadotropin-releasing hormone receptor to elicit its biologic response, which is the release of the pituitary hormones FSH and LH. However, two or three weeks after their continous administration, a profound hypogonadal effect, e.g., the depletion of gonatrophins, is achieved by receptor downregulation. Inducing superagonism at an early stage, this mechanism cannot avoid the initial concomitance of side effects.
GnRH receptor antagonists that exert direct antagonistic effects have been suggested as an alternative. When administered, they can immediately decrease the level of gonatrophins without any initial side effects. However, they suffer from the disadvantages of being of relatively low bioavailability in clinical use and stimulating histamine release. There have been reports of peptidyl antagonists which have a low histamine release, but they must be taken by parenteral administration routes, such as intravenous, subcutaneous or intramuscular injection, due to their low bioavailability.
Only recently have non-peptidyl compounds been suggested for overcoming the limitations of the peptidyl antagonists (see Expert Opin. Ther. Patents 16(6): 733-751, 2006). In spite of lots of studies in this field, there still remains a need for low-molecular weight GnRH receptor antagonists with good bioavailability. The present invention revolves around this substantial need.